Tetracyclines lipid solubility

Doxycycline (6-deoxy-5-hydroxytetracycline, Vibramycin, III) is, chemically, the most stable tetracycline in current use but its outstanding property is its high lipid solubility these features combine to make it the most reliably and completely absorbed tetracycline derivative, with the longest half-life. 

Drugs that may interact with laxatives include mineral oil, milk or antacids, H2 antagonists, proton pump inhibitors, lipid soluble vitamins (A, D, E, and K), and tetracycline. 

We have already met several of the important concepts in this topic, so now it is time to round them up and bring out the major principles. In the first place drug molecules clearly might interact with food molecules in the lumen of the gut. Perhaps the best-known example of this is the interaction between the tetracyclines and dietary calcium and iron. The binding, which occurs between them, produces a chelate, which is not particularly lipid-soluble, and therefore the overall absorption of tetracycline may be reduced to the point where plasma levels do not achieve effective antibiotic concentrations. The commonest dietary constituent to produce this binding is milk with its high calcium content. Tetracycline ingestion should be separated from food as far as possible. 

The tetracyclines are distributed throughout body tissues and fluids in concentrations that reflect the lipid solubility of each individual agent. Minocycline and doxycycline are the most lipid soluble, while oxytetracy-chne is the least hpid soluble. The tetracyclines penetrate (but somewhat unpredictably) the uninflamed meninges and cross the placental barrier. Peak serum levels are reached approximately 2 hours after oral administration cerebrospinal fluid (CSF) levels are only one-fourth those of plasma. 

It seems reasonable to assume that the mechanisms may be similar to that postulated for tetracyclines, which reduce cerebrospinal fluid absorption, possibly by an effect on cyclic adenosine monophosphate at the arachnoid villi (6). Minocycline crosses the blood-brain barrier more effectively than other tetracyclines, because of its greater lipid solubility. Therefore, a physician who prescribes minocycline should keep his eye on the patient s eyes. 

The lipid solubility of four tetracyclines (minocycline, doxycycline, tetracycline and oxytetracycline) correlates inversely with the mean concentration of antibiotic in plasma and with renal uptake and excretion. Only the more lipophilic minocycline and doxycycline pass across the blood-brain and blood-ocular barriers in detectable concentrations. Table 5.19 gives some of these characteristics of the tetracyclines. These analogues of tetracycline, while active in vitro against meningococci, are... 

The tetracyclines are distributed into most tissues, except the CNS (therapeutic levels may be achieved when the meninges are inflamed). Doxycycline is the most lipid-soluble tetracycline... 

Rapid i.v. administration of tetracyclines can result in hypotension and collapse. This has been attributed to intravascular chelation of calcium and/or a decrease in blood pressure owing to the drug vehicle. The i.v. administration of doxycycline to horses causes tachycardia, systemic arterial hypertension, collapse and death. This reaction may be caused by the highly lipid-soluble doxycycline chelating intracellular calcium, resulting in cardiac neuromuscular blockade. 

Minocycline is another commonly prescribed oral antibiotic used in the treatment of moderate to severe acne vulgaris. It is more effective than tetracycline because of greater lipid solubility and enhanced penetration into tissne and sebaceons foUicles. It is dosed similarly to doxycycline (100 mg/day or 50 mg twice daily) and on an indefinite basis in selected patients. 

Doxycycline is more lipid-soluble than other tetracyclines and less dependent on renal elimination more than 50% of the drug is eliminated in the feces. 

In a cell-free system inhibition can be shown to occur on both 70S and 80S ribosomes. However, in a more realistic in vitro setting intact prokaryotic (i.e., bacterial) cells are much more sensitive. The reason for this selectivity is that tetracyclines are actively transported into bacterial but not mammalian cells. In Gm- bacteria, at least, the more water-soluble compounds seem to cross through membrane channels (pores). The more lipid-soluble drugs (particularly MNC, Table 6-9) diffuse more readily through the lipoidal phases of the membranes. This energy-coupled process then leads to intracellular antibiotic accumulations. 

The pH-partition hypothesis relating to membrane penetrability was outlined in Chapter 1. This hypothesis would allow one to make reasonable assumptions of a drug s behavior whose pKa and aqueous-lipid partition were determined. The amphoteric nature of tetracyclines with their multiple pKas, however, presents a more complex situation than simply improving lipid solubility by the deletion of polar hydroxyl groups from positions such as 5 and 6 (e.g., DC, MC, MNC) or the addition of a halogen on C-7 (e.g., DMCTC, CTC). 

The absorption of tetracyclines from the G1 tract is non-uniform. Up to 30% of chlortetracycline is absorbed. The absorption for tetracycline, oxytetracycline, and demeclo-cycline ranges between 60 and 80%, whereas as much as 90 to 100% of doxycycline and minocycline is absorbed. The absorption of tetracyclines is impaired by divalent cations (calcium, magnesium, and ferrous iron), by aluminum, and by extremely alkaline pHs. Tetracyclines are distributed widely throughout the body fluid, cross the placental barrier, and can accumulate in growing bones. The concentrations of chlortetracycline in spinal fluid are only one fourth of those in plasma. Minocycline, a more lipid-soluble tetracycline, reaches a high concentration in tears and saliva and can eradicate the meningococcal carrier state. The tetracyclines are metabolized in the liver and excreted mainly by the bile and urine. The concentrations of tetracyclines in the bile are ten times higher than those in serum. 

Drugs of the tetraeycline group are amphoteric, forming salts with both acids and bases. They are used as parent compounds (e.g., oxytetracycline dihydrate) or as salts (e.g., oxytetracycline hydrochloride). Their lipid solubilities range from moderate (oxytetracycline and chlortetracycline) to high (doxycycline and minocycline), so that they are able to traverse cell membranes moderately or readily. The former two drugs are natural tetracyclines, while the latter two are semi-synthetic. 

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